دورية أكاديمية
أعرض في EDS

PLK1 Inhibition Targets Myc-Activated Malignant Glioma Cells Irrespective of Mismatch Repair Deficiency-Mediated Acquired Resistance to Temozolomide.

التفاصيل البيبلوغرافية
العنوان: PLK1 Inhibition Targets Myc-Activated Malignant Glioma Cells Irrespective of Mismatch Repair Deficiency-Mediated Acquired Resistance to Temozolomide.
المؤلفون: Higuchi F; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Fink AL; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Kiyokawa J; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Miller JJ; Stephen E. and Catherine Pappas Center for Neuro-Oncology, Division of Hematology/Oncology, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts., Koerner MVA; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Cahill DP; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. hwakimoto@mgh.harvard.edu cahill@mgh.harvard.edu., Wakimoto H; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. hwakimoto@mgh.harvard.edu cahill@mgh.harvard.edu.
المصدر: Molecular cancer therapeutics [Mol Cancer Ther] 2018 Dec; Vol. 17 (12), pp. 2551-2563. Date of Electronic Publication: 2018 Sep 14.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Association for Cancer Research, Inc Country of Publication: United States NLM ID: 101132535 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1538-8514 (Electronic) Linking ISSN: 15357163 NLM ISO Abbreviation: Mol Cancer Ther Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Philadelphia, PA : American Association for Cancer Research, Inc., c2001-
مواضيع طبية MeSH: DNA Mismatch Repair*/drug effects , Drug Resistance, Neoplasm*/drug effects, Cell Cycle Proteins/*antagonists & inhibitors , Glioma/*drug therapy , Glioma/*pathology , Protein Serine-Threonine Kinases/*antagonists & inhibitors , Proto-Oncogene Proteins/*antagonists & inhibitors , Proto-Oncogene Proteins c-myc/*metabolism , Temozolomide/*therapeutic use, Animals ; Biomarkers, Tumor/metabolism ; Cell Cycle Checkpoints/drug effects ; Cell Cycle Proteins/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; DNA Damage ; DNA-Binding Proteins/metabolism ; Down-Regulation/drug effects ; Female ; Gene Silencing/drug effects ; Humans ; Mice, Nude ; Mitosis/drug effects ; Protein Kinase Inhibitors/pharmacology ; Protein Serine-Threonine Kinases/metabolism ; Proto-Oncogene Proteins/metabolism ; Pteridines/pharmacology ; Temozolomide/pharmacology ; Up-Regulation/drug effects ; Polo-Like Kinase 1
مستخلص: Mismatch repair (MMR) deficiency through MSH6 inactivation has been identified in up to 30% of recurrent high-grade gliomas, and represents a key molecular mechanism underlying the acquired resistance to the alkylating agent temozolomide (TMZ). To develop a therapeutic strategy that could be effective in these TMZ-refractory gliomas, we first screened 13 DNA damage response modulators for their ability to suppress viability of MSH6-inactivated, TMZ-resistant glioma cells. We identified a PLK1 selective inhibitor, Volasertib, as the most potent in inhibiting proliferation of glioblastoma cells. PLK1 inhibition induced mitotic catastrophe, G 2 -M cell-cycle arrest, and DNA damage, leading to caspase-mediated apoptosis in glioblastoma cells. Importantly, therapeutic effects of PLK1 inhibitors were not influenced by MSH6 knockdown, indicating that their action is independent of MMR status of the cells. Systemic treatment with Volasertib potently inhibited tumor growth in an MMR-deficient, TMZ-resistant glioblastoma xenograft model. Further in vitro testing in established and patient-derived cell line panels revealed an association of PLK1 inhibitor efficacy with cellular Myc expression status. We found that cells with deregulated Myc are vulnerable to PLK1 inhibition, as Myc overexpression sensitizes, whereas its silencing desensitizes, glioblastoma cells to PLK1 inhibitors. This discovery is clinically relevant as glioma progression post-TMZ treatment is frequently accompanied by MYC genomic amplification and/or pathway activation. In conclusion, PLK inhibitor represents a novel therapeutic option for recurrent gliomas, including those TMZ-resistant from MMR deficiency. Genomic MYC alteration may serve as a biomarker for PLK inhibitor sensitivity, as Myc-driven tumors demonstrated pronounced responses.
(©2018 American Association for Cancer Research.)
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معلومات مُعتمدة: R01 CA227821 United States CA NCI NIH HHS
المشرفين على المادة: 0 (BI 6727)
0 (Biomarkers, Tumor)
0 (Cell Cycle Proteins)
0 (DNA-Binding Proteins)
0 (G-T mismatch-binding protein)
0 (Protein Kinase Inhibitors)
0 (Proto-Oncogene Proteins)
0 (Proto-Oncogene Proteins c-myc)
0 (Pteridines)
EC 2.7.11.1 (Protein Serine-Threonine Kinases)
YF1K15M17Y (Temozolomide)
تواريخ الأحداث: Date Created: 20180916 Date Completed: 20190910 Latest Revision: 20231213
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC6279590
DOI: 10.1158/1535-7163.MCT-18-0177
PMID: 30217967
قاعدة البيانات: MEDLINE
الوصف
تدمد:1538-8514
DOI:10.1158/1535-7163.MCT-18-0177